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Caspase-1-dependent pyroptosis of peripheral blood mononuclear cells predicts the development of sepsis in severe trauma patients: A prospective observational study.

ABSTRACT: Pyroptosis plays a pivotal role in sepsis and septic shock in animal studies. However, its clinical significance in pathological conditions has not been well elucidated. This study aimed to evaluate the correlation between the percentage of pyroptotic peripheral blood mononuclear cells (PBMCs) and the clinical index and to investigate the relationship between PBMCs pyroptosis and the development of sepsis in trauma patients.This prospective study was conducted from October 2016 to May 2017 in a comprehensive trauma center. Sixty trauma patients and 10 healthy controls were enrolled. Peripheral blood samples were collected from the patients within 24 hours after injury. The percentages of pyroptotic and apoptotic PBMCs were measured using flow cytometry, and plasma levels of cytokines were evaluated using flow cytometric analysis with a human inflammation 13-plex panel.Trauma patients who developed sepsis had higher percentages of pyroptotic and apoptotic PBMCs at admission. Patients who developed sepsis (n = 33) had higher interleukin (IL)-6, IL-18, and monocyte chemotactic protein-1 (MCP-1) concentrations at admission than patients (n = 27) who did not develop sepsis. The percentage of PBMCs pyroptosis was significantly correlated with injury severity score (ISS), acute physiology and chronic health evaluation (APACHE) II score, IL-10, IL-18, and MCP-1 levels in trauma patients. PBMCs pyroptosis is a better biomarker in predicting the development of sepsis after trauma.This study indicates that the percentage of pyroptotic PBMCs increases during the early phase of trauma and that this increase is significantly correlated with the severity and state of inflammation in trauma patients. PBMCs pyroptosis is a potential marker for predicting the development of sepsis after trauma.

SUBMITTER: Wang YC

PROVIDER: S-EPMC5841964 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:OBJECTIVES:Metabolic derangements in sepsis stem from mitochondrial injury and contribute significantly to organ failure and mortality; however, little is known about mitochondrial recovery in human sepsis. We sought to test markers of mitochondrial injury and recovery (mitochondrial biogenesis) noninvasively in peripheral blood mononuclear cells from patients with sepsis and correlate serial measurements with clinical outcomes. DESIGN:Prospective case-control study. SETTING:Academic Medical Center and Veterans Affairs Hospital. PATIENTS:Uninfected control patients (n = 20) and septic ICU patients (n = 37). INTERVENTIONS:Blood samples were collected once from control patients and serially with clinical data on days 1, 3, and 5 from septic patients. Gene products for HMOX1, NRF1, PPARGC1A, and TFAM, and mitochondrial DNA ND1 and D-loop were measured by quantitative reverse transcriptase-polymerase chain reaction. Proinflammatory cytokines were measured in plasma and neutrophil lysates. MEASUREMENTS AND MAIN RESULTS:Median (interquartile range) Acute Physiology and Chronic Health Evaluation II and Sequential Organ Failure Assessment scores were 21 (8) and 10 (4), respectively, and 90-day mortality was 19%. Transcript levels of all four genes in peripheral blood mononuclear cells were significantly reduced in septic patients on day 1 (p < 0.05), whereas mitochondrial DNA copy number fell and plasma D-loop increased (both p < 0.05), indicative of mitochondrial damage. D-loop content was directly proportional to tumor necrosis factor-α and high-mobility group protein B1 cytokine expression. By day 5, we observed transcriptional activation of mitochondrial biogenesis and restoration of mitochondrial DNA copy number (p < 0.05). Patients with early activation of mitochondrial biogenesis were ICU-free by 1 week. CONCLUSIONS:Our findings support data that sepsis-induced mitochondrial damage is reversed by activation of mitochondrial biogenesis and that gene transcripts measured noninvasively in peripheral blood mononuclear cells can serve as novel biomarkers of sepsis recovery.

Project description:OBJECTIVES:One third of infrainguinal vein bypasses may fail within the first 1.5 years. Pro- and anti-inflammatory mechanisms are thought to be involved in these graft stenoses and occlusions. In previous studies, low levels of anti-phosphorylcholine IgM (anti-PC IgM, an innate anti-inflammatory IgM) have been associated with increased cardiovascular events. In this study, the peri-operative dynamics of anti-PC IgM levels were established during leg bypass surgery, and associations assessed between anti-PC IgM levels and primary graft patency. DESIGN AND METHODS:This was a prospective, observational cohort study of infrainguinal autogenous vein bypass for peripheral arterial occlusive disease involving four university affiliated hospitals. Plasma cytokine and anti-PC IgM levels were measured pre- and post-operatively. The outcome of interest was loss of primary graft patency because of occlusion or intervention for graft stenosis. RESULTS:One hundred and forty-two consecutive patients were enrolled: mean age 66 (46-91); 91% white race and male; 72.5% critical limb ischaemia (Fontaine III or IV). Median pre-operative anti-PC IgM levels were 49 units/mL (IQR 32.3-107.7, mean 89.8 + 101 sd). During follow up of an average of 1.8 years (1 month-7.4 years), 50 (35.2%) grafts lost primary patency. Pre-operative levels of interleukin 6 or C-reactive protein did not predict graft failure. Patients with pre-operative anti-PC IgM values in the lowest quartile had a twofold increased risk of graft failure (multivariable Cox proportional hazard, p = .03, HR 2.11, 95% CI 1.09-4.07), even after accounting for the other significant factors of conduit diameter, distal anastomosis, smoking, and the severity of leg ischaemia. CONCLUSIONS:Low levels of anti-PC IgM are associated with vein bypass graft failure. This biological mediator may be a useful marker to identify patients at higher risk, and offers the potential for novel, directed therapies for vascular inflammation and its consequences.

Project description:Background: Sepsis, as a clinical emergency, usually causes multiorgan dysfunction and can lead to high mortality. Establishment of specific and sensitive biomarkers for early diagnosis is critical to identify patients who would benefit from targeted therapy. In this study, we investigated this syndrome by analyzing the transcriptome of peripheral blood mononuclear cells (PBMCs) from patients with sepsis and identified sepsis-specific biomarkers. Methods: In this study, a total of 87 patients with sepsis and 40 healthy controls from a prospective multicenter cohort were enrolled. Samples from 44 subjects (24 patients with sepsis and 20 healthy controls) were sequenced and the remaining patients were included in the validation group. Using high-throughput sequencing, a gene expression profile of PBMCs from patients with sepsis was generated to elucidate the pathophysiology of sepsis and identify sepsis-specific biomarkers. Results: Principal component analysis (PCA) and unsupervised hierarchical cluster analysis showed that patients with sepsis separated from healthy controls. A total of 1639 differentially expressed genes (DEGs) were identified (|log2 fold change|>2, adjusted P value <0.05) between these two groups, with 1278 (78.0%) upregulated and 361 (22.0%) downregulated in patients with sepsis. Gene Ontology (GO) analysis of the upregulated DEGs identified 194 GO terms that were clustered into 27 groups, and analysis of the downregulated DEGs identified 20 GO terms that were clustered into 4 groups. Four unique genes were identified that could be predictive of patients with sepsis. External validation of the four genes using quantitative real-time polymerase chain reaction (qRT-PCR) was consistent with the results of mRNA sequencing, revealing their potential in sepsis diagnosis. Conclusions: The transcriptome characteristics of PBMCs, which were significantly altered in sepsis patients, provide new insights into sepsis pathogenesis. The four identified gene expression changes differentiated patients with sepsis from healthy subjects, which could serve as a convenient tool contributing to sepsis diagnosis.

Project description:BackgroundContinuous monitoring of central venous oxygen saturation (ScvO2) has been proposed as a prognostic indicator in several pathological conditions, including cardiac diseases, sepsis, trauma. To our knowledge, no studies have evaluated ScvO2 in polytraumatized patients with brain injury so far. Thus, the aim of the present study was to assess the prognostic role of ScvO2 monitoring during first 24 hours after trauma in this patients' population.MethodsThis prospective, non-controlled study, carried out between April 2006 and March 2008, was performed in a higher level Trauma Center in Florence (Italy). In the study period, 121 patients affected by major brain injury after major trauma were recruited. Inclusion criteria were: 1. Glasgow Coma Scale (GCS) score <or= 13; 2. an Injury Severity Score (ISS) >or= 15. Exclusion criteria included: 1. pregnancy; 2. age < 14 years; 3. isolated head trauma; 4. death within the first 24 hours from the event; 5. the lack of ScvO2 monitoring within 2 hours from the trauma. Demographic and clinical data were collected, including Abbreviated Injury Scale (AIS), Injury Severity Score (ISS), Simplified Acute Physiologic Score II (SAPS II), Marshall score. The worst values of lactate and ScvO2 within the first 24 hours from trauma, ICU length of stay (LOS), and 28-day mortality were recorded.ResultsPatients who deceased within 28 days showed higher age (53 +/- 16.6 vs 43.8 +/- 19.6, P = 0.043), ISS core (39.3 +/- 14 vs 30.3 +/- 10.1, P < 0.001), AIS score for head/neck (4.5 +/- 0.7 vs 3.4 +/- 1.2, P = 0.001), SAPS II score (51.3 +/- 14.1 vs 42.5 +/- 15, P = 0.014), Marshall Score (3.5 +/- 0.7 vs 2.3 +/- 0.7, P < 0.001) and arterial lactate concentration (3.3 +/- 1.8 vs 6.7 +/- 4.2, P < 0.001), than survived patients, whereas ScvO2 resulted significantly lower (66.7% +/- 11.9 vs 70.1% +/- 8.9 vs, respectively; P = 0.046). Patients with ScvO2 values <or= 65% also showed higher 28-days mortality rate (31.3% vs 13.5%, P = 0.034), ICU LOS (28.5 +/- 15.2 vs 16.6 +/- 13.8, P < 0.001), and total hospital LOS (45.1 +/- 20.8 vs 33.2 +/- 24, P = 0.046) than patients with ScvO2 > 65%.ConclusionScvO2 value less than 65%, measured in the first 24 hours after admission in patients with major trauma and head injury, was associated with higher mortality and prolonged hospitalization.

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Caspase-1-dependent pyroptosis of peripheral blood mononuclear cells predicts the development of sepsis in severe trauma patients: A prospective observational study.

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